A Difference in Heterosubtypic Immunity Induced by a Modified Live Attenuated Avian Influenza Backbone in Mice and Ferrets
Perez, Daniel R
MetadataShow full item record
The unprecedented emergence of multiple avian influenza virus (AIV) subtypes with a broad host range poses a major challenge in the design of vaccination strategies that are effective against multiple subtypes of influenza. The present study focused on the protective effects of a modified AIV as a backbone for epidemic and pandemic influenza. In addition, the ability of this backbone to induce heterosubtypic immunity (Het-I) was also analyzed. Het-I is the ability of one influenza subtype to protect against a different influenza subtype. Previously, a live attenuated AIV with the internal backbone of A/guinea fowl/Hong Kong/WF10/99 (H9N2) (WF10), called WF10<italic>att</italic>, protected chickens against a lethal influenza challenge. To characterize the WF10<italic>att</italic> backbone as a master donor strain and determine its ability to induce Het-I, we evaluated its protective efficacy in mice and ferrets. Vaccinated mice were protected against homologous challenge with A/WSN/1933 (H1N1) (WSN), mouse-adapted A/California/04/2009 (pH1N1) and A/Vietnam/1203/2004 (H5N1) (HPAI H5N1) viruses, and ferrets survived homologous challenge with HPAI H5N1. H7N2<italic>att</italic> vaccinated mice were protected against both H1N1 and HPAI H5N1 challenge; however, Het-I was observed in H9N2<italic>att</italic> vaccinated ferrets challenged with HPAI H5N1. We found that both B and T cells are involved in the Het-I induced by our WF10<italic>att</italic> backbone. Cross-reactive non-neutralizing antibodies to viral proteins were detected. JhD<super>-/-</super> mice, which lack mature B-lymphocytes, were vaccinated with the recombinant vaccines and challenged with HPAI H5N1. None of the vaccinated mice survived challenge further suggesting a role for Het-I. In addition, cells isolated from the lungs of H7N2<italic>att</italic> vaccinated mice had cross-reactive antibody-secreting cells targeted to HPAI H5N1. Together, these results suggest a role for B cells in Het-I. Although B cells are important, T cells may also play a role in Het-I. Both IFN-γ and Granzyme B secreting cells were detected in lung and spleen cells isolated from H7N2att vaccinated mice and stimulated with HPAI H5N1 suggesting a role for T cells in Het-I. The ability of our WF10<italic>att</italic> backbone to induce Het-I depends on the surface glycoproteins expressed and the challenge virus subtype. In addition, WF10<italic>att</italic> uses both B and T cells to induce Het-I.